The potential role of microbicides in preventing the mucosal transmission of HIV-l has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. A comprehensive program for preclinical development of microbicide candidates, therefore, requires that information be accrued from several different model systems. Dr Shattock's group has established human mucosal explant cultures as a model system for the evaluation of potential microbicides and has already used them to assess the properties of microbicide that are currently entering Phase II and III clinical trials. Such explants are highly susceptible to HIV-1 infection in vitro. Cells present within the explants represent the immune population first exposed to HIV-l during sexual transmission in terms of their phenotype (e.g., co-receptor expression), state of activation an anatomical location. Thus, as a model, it directly reflects what happens during mucosal challenge of human with HIV-1. The goal of this Research Project is the evaluation of specific inhibitors of HIV-1 attachment, fusion and entry (AFE inhibitors) for their potential as mucosal microbicides to prevent sexual transmission of HIV-1 infection.